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Melanoma is the most common malignant skin cancer, appears indestructible and is notoriously resistant to all current modalities of cancer treatment strategies. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor, has shown to have radiosensitizing properties for a variety of cancers. Recently, we have shown that PTX exhibits antimetastatic and anti-angiogenic activities in B16F10 melanoma cells in vitro as well as in vivo. In the present study, we have demonstrated the anticancer and antimetastatic potential of PTX against A375 human melanoma cell line at sub-toxic doses. The results implicate that PTX at sub-toxic doses exhibited an inhibitory effect on the ability of cellular proliferation as shown by MTT and colony formation assay. It impedes migration and also induces apoptosis. A375 cells pretreated with PTX showed decrease in adhesion to both Matrigel and Collagen type IV. Further, Gelatin zymography result reveals that PTX treatment decreases the secretion of MMP2 and MMP9. Finally, PTX significantly inhibited A375 subcutaneous tumour xenograft growth without having any toxicity. Thus PTX at sub-toxic doses affected melanoma metastasis at multiple steps in vitro as well as tumour growth in vivo. These data demonstrate its antimetastatic potential and provide preclinical evidence for the development of PTX as a potential agent against metastatic melanoma.
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The data collected during this double-blind study point to an immunomodulatory role of PTX, the beneficial effect on graft survival resulting from a restraining effect of the drug on the inflammatory conditions involved in acute graft rejection.
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To establish an in vivo method for matrix metalloproteinase (MMP)-2 and MMP-9 induction in horses via IV administration of lipopolysaccharide (LPS) and to evaluate the ability of doxycycline, oxytetracycline, flunixin meglumine, and pentoxifylline to inhibit equine MMP-2 and MMP-9 production.
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The frostbitten ears of 10 New Zealand white rabbits were assigned to one of four treatment groups: untreated controls, those treated with aloe vera cream, those treated with pentoxifylline, and those treated with aloe vera cream and pentoxifylline.
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Two patients with idiopathic livedo vasculitis responded favorably to therapy with pentoxifylline. One patient had responded to fibrinolytic therapy with phenformin and ethylestrenol before phenformin was taken off the market. Pentoxifylline (Trental) has multiple mechanisms of action, including stimulation of prostacyclin synthesis, decreased aggregation of platelets, increased deformability of red blood cells, increased mobility of neutrophils, and increased fibrinolysis. All of these factors may contribute to its successful use in the treatment of idiopathic livedo vasculitis.
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This study showed that the tincture of Operculina macrocarpa has antiplatelet effect that cannot be attributed to a single biochemical mechanism and at least part of it cannot be related to the OMT inhibition of P2Y12 purinergic receptors.
The primary objective of this review was to determine the effect of pentoxifylline on the incidence of BPD, death prior to 36 weeks postmenstrual age (PMA), and BPD or death prior to 36 weeks PMA in preterm neonates.
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The present study is the first prospective randomized controlled trial of the effect of pentoxifylline on future fertility in infertile women with asymptomatic minimal or mild endometriosis. After completion of a basic infertility workup and laparoscopy, patients were entered into the study and randomly allocated to receive either a 12 month course of oral pentoxifylline (800 mg/day) (n = 30) or an oral placebo (n = 30). Those patients with other infertility factors were included in the study only if the factors were correctable and ultimately determined to be non-contributory. Life-table analysis was used to compare pregnancy rates between the two groups over a 12 month period that started immediately after laparoscopy. The 12 month actuarial overall pregnancy rates were 31 and 18.5% in the pentoxifylline and placebo groups respectively. However, this difference was not statistically significant by the chi(2)-test. Similarly, the Cox regression method showed no differences between the hazard of pregnancy in the two groups studied (odds ratio, 0.56; 95% confidence interval, 0.18-1.67). Therefore, there is no evidence from this study that immunomodulation with pentoxifylline aids fertility in those women with minimal or mild endometriosis. Further studies including more infertile patients with endometriosis are desirable in order to confirm our results.
Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The mainstay of treatment has been management of hyperglycaemia, blood pressure and proteinuria using hypoglycemic agents, ACE inhibitors, and angiotensin receptor blockers. Since 2000, new therapeutic strategies began to emerge targeting the biochemical activity of glucose molecules on the renal tissue. Various substances have been studied with varying degrees of success, ranging from vitamin B to camel's milk. Silymarin reduces urinary excretion of albumin, tumor necrosis factor (TNF)-α, and malondialdehyde in patients with diabetic nephropathy and may be considered as a novel addition to the anti-diabetic nephropathy armamentarium. Although some results are promising, studies on a larger scale are needed to validate the utility of these molecules in the treatment of the DN.
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Chronic recurrent oral aphthous ulcers are the most common type of inflammatory efflorescence of the oral mucosa, with a prevalence of 2% to 10% in Caucasian populations. To treat them properly, physicians should know their clinical appearance and course, conditioning factors, underlying causes, and differential diagnosis.
It has been reported experimentally that application of nucleus pulposus into epidural space induces morphologic and functional changes in the nerve roots and induces compartment syndrome in the dorsal root ganglia. Tumor necrosis factor-alpha has been considered a key pathogenic factor in the initiation and maintenance of neuropathic pain states.
Following drug administration, initial decreases in MABP down to 75% of baseline values were observed for all three substances. PX, HW, and TB caused initial transient reductions in mean RBC flux followed by gradual increases to values of 137 +/- 27%, 139 +/- 14%, and 122 + 14% respectively at t = 60 min. Following a small initial decrease upon drug administration, O2 partial pressure (pO2) rose to 160 +/- 31%, 153 +/- 34%, and 121 +/- 11% for PX, HW, and TB, respectively at t = 60 min. At the end of the observation period (t = 90 min), increases in RBC flux and pO2 were still evident. When individual tumors were considered, a variety of patterns (including opposing effects) for changes in RBC flux were seen, not necessarily reflected in the mean values. Thus, while the methylxanthine derivatives caused an increased average tumor perfusion, there is evidence suggesting that a redistribution of tumor blood flow occurs which may amplify preexisting heterogeneity.
In animal experiments the effects of Echinacin, a sap made from Herba recens Echinaceae purpureae, on the rate of necrosis of skin flaps were studied in comparison with NaCl and pentoxifylline. The fluoresceine test was used as an indicator of peripheral circulation. The noncirculated area of the skin flap was significantly smaller in Herba Echinaceae treated animals than in control animals (p less than 0.01). On the day of the operation the size of the noncirculated flap area was only 56.0%, whereas it was 77.8% in the NaCl group and 67.4% in the pentoxifylline group. Until the 5th postoperative day the ratios changed to 47.4% (Herba Echinaceae), 76.6% (NaCl) and 50.4% (pentoxifylline). While more than two thirds of the skin flap area were to become necrotic in the NaCl group, less than half of the skin flap was so in the Herba Echinaceae group. Thus Herba Echinaceae significantly decreased the rate of necrosis of skin flaps in animal experiments.
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Two review authors independently extracted data and assessed trial quality.
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This pilot investigation points to the effectiveness of pentoxifylline as an adjunct therapy in the routine management of oral submucous fibrosis.
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Topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal epidermis of Sencar mice induces synthesis of pro-inflammatory cytokines, including interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha). These proteins differentially regulate proliferation of epidermal keratinocytes, as well as stimulate chemotaxis, migration and production of reactive oxygen and nitrogen intermediates by leukocytes. Studies over the past several years have demonstrated that pentoxifylline ([1-(5-oxohexyl)-3,7-dimethyl-xanthine], oxpentifylline), which is a methylxanthine derivative used clinically for treatment of vascular insufficiency, has the unique ability to inhibit synthesis of pro-inflammatory cytokines. The present studies were performed to examine the effects of acute and chronic administration of pentoxifylline on TPA-induced cutaneous inflammation in female Sencar mice treated once with 10 micrograms TPA and also to determine the ability of pentoxifylline to inhibit the tumor promotion process in mice treated with a single application of 25 nmol 7,12-dimethylbenz[a]anthracene (DMBA) followed for 8 weeks by twice weekly topical application of TPA. Intraperitoneal injection of 50 micrograms/g pentoxifylline at 30 min prior to topical application of 10 micrograms TPA to the dorsal epidermis of Sencar mice inhibited TPA-induced IL-1 alpha and TNF-alpha gene expression 24 h after TPA treatment. Administration of pentoxifylline also significantly inhibited all parameters of acute TPA-induced inflammatory response examined 24 h later, including skin thickening (P < 0.005), infiltration of neutrophils into the dermis (P < 0.001), the corresponding dermal myeloperoxidase activity (P < 0.01) and epidermal hyperplasia (P < 0.001). Injection of 50 micrograms/g pentoxifylline over an 8 week time period significantly inhibited DMBA/TPA-induced papilloma growth (P < 0.05). These results indicate that administration of pentoxifylline is an effective means of inhibiting acute TPA-induced cutaneous inflammation and pro-inflammatory cytokine gene expression, as well as is effective as an antipromoter that inhibits papilloma growth.
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Chemosensitivity of the human adenocarcinoma cell line MOR/P and the cisplatin-resistant subline MOR/CPR as well as the large-cell lung cancer cell line L23/P and its cisplatin-resistant counterpart L23/CPR were evaluated by the MTT colorimetric assay.
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The microcirculatory state (by the method of conjunctival biomicroscopy) and ADP-induced platelet aggregation were examined in 42 patients with atherosclerotic and 34 patients with involutional depression both before and after the treatment which included vasoactive preparations and calcium antagonists. It was determined vascular and intravascular alterations predominance and increase of platelet aggregation in patients with atherosclerotic depression independently of leading syndrome, in patients with involutional depression with anxiety prevalence as well as in patients in stuporous state. The tendency was revealed of such disturbances increasing as for as psychosis was extended. Trental and Cavinton antiplatelet and spasmolytic properties were potentiated by inclusion of Corinfar in complex therapy and that promoted earlier microcirculatory alterations removal as well as aggregatograms and patient mental state normalization.
Hemorheological Treatment in Vertigo. Depending on data of hemorheology disturbances in risk factors (1.2.3.) and carotid artery arterosclerosis--progression in vertigo of non-vestibular origin (4.) this study evaluates treatment effects by basis, i.e. correction of risk factors only, versus additional hemorheological treatment (Lowering hct., HAES, Pentoxifylline) Patients: N = 88 fe. 51 m 37 age 25-86 mean 65.1.
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Pentoxifylline (Pent) is a xanthine known to improve erythrocyte deformability and thought to have little effect on smooth muscle tone. In this study I examined the direct effects of Pent on the pulmonary vasculature of isolated lungs and compared them with the effects of aminophylline. The object was to study whether Pent can reverse the hypoxic pressor response (HPR) by its hemorheological property. Changes in pulmonary arterial pressure (Pa) of isolated lungs (pigs and rats) perfused at constant flow rate were monitored to reflect changes in vascular resistance. During normoxia, injection of Pent (5 mg/kg animal weight) in pig lungs depressed the Pa from 12.8 +/- 1.8 to 8.1 +/- 0.8 mmHg (1 mmHg = 133.3 Pa); whereas during hypoxia, Pa was depressed from 34.0 +/- 2.3 to 12.3 +/- 1.4 mmHg. To identify the mechanism of this vasodepressor effect (being either vasodilation or improved erythrocyte deformability), I tested the effect of Pent in lungs perfused with cell-free perfusate. In these plasma-perfused lungs, the vasodepressor effects of Pent were similar to those observed during blood perfusion (slight depression in Pa during normoxia, but large during hypoxia). Similar experiments in blood and plasma perfused pig lungs revealed that aminophylline (5 mg/kg) also produced similar vasodepressor responses. The effects of Pent in rat lungs were comparable; no effect during normoxia, but a depressor effect during hypoxia. Vasoconstriction in pig lungs induced by angiotensin infusion was also abolished by Pent.(ABSTRACT TRUNCATED AT 250 WORDS)
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We have studied the effect of an inhibitor of matrix metalloproleinases, BB-1101, on a delayed-type hypersensitivity (DTH) response in the CNS. We used a recently described model in which heat-killed bacillus Calmette-Guérin (BCG) sequestered behind the blood-brain barrier (BBB) is targeted by a T-cell mediated response after subcutaneous injection of BCG (Matyszak and Perry, 1995). The DTH lesions are characterised by breakdown of the BBB, macrophage and lymphocyte infiltration and tissue damage including myelin loss. Treatment with BB-1101, which is not only a potent inhibitor of matrix metalloproteinases but also strongly inhibits TNF-alpha release, dramatically attenuated the CNS lesions. Breakdown of the BBB and the recruitment of T-cells into the site of the lesion were significantly reduced. There were many fewer inflammatory macrophages in DTH lesions than in comparable lesions from untreated animals. There was also significantly less myelin damage (assessed by staining with anti-MBP antibody). The DTH response in animals treated with dexamethasone was also reduced, but to a lesser degree. No significant effect was seen after administration of pentoxifylline, a phosphodiesterase inhibitor with effects including the inhibition of TNF-alpha production. Our results suggest that inhibitors of matrix metalloproteinases may be of considerable therapeutic benefit in neuroinflammatory diseases.
Rats are commonly used in anaphylaxis models, mainly in intestinal anaphylaxis. Hypersensitivity mechanisms are complex and they are not clearly defined. Ovalbumin (OVA) is commonly used for studies on the hypersensitivity mechanism. However, the potential pro-inflammatory mediators induced by this antigen in the model of paw oedema in immunized rats are still not completely understood. This work examines the pharmacological modulation of several mediators involved in rat hind paw immune oedema induced by OVA. Wistar rats were previously immunized (14-18 days) with OVA (30 microg, intraperitoneally) or sham-sensitized with aluminum hydroxide (control). The paw volumes were measured before the antigenic stimuli and 1, 2, 3 and 4 h after the intraplantar injection of OVA (10 microg/paw). Subcutaneous injection of dexamethasone, diphenhydramine, cyproheptadine, chlorpromazine or methysergide significantly inhibited (p < 0.05) the allergic paw oedema. The dual inhibitor of cyclooxygenase and lipoxygenase (NDGA), the cyclooxygenase inhibitor (indomethacin), the lipoxygenase inhibitor (MK-886), the PAF antagonist (WEB 2086), the mast cell stabilizer (ketotifen), and the anti-histamine (meclizine) did not inhibit the immune oedema. In addition, thalidomide and pentoxifylline (anti-tumour necrosis factor drugs) were ineffective against OVA-induced oedema. The fact that indomethacin, MK-886, NDGA and WEB 2086 are unable to inhibit this allergic oedema indicates that the dexamethasone action seems not to be via phospholipase A2, but possibly due to the synthesis and/or the inhibitory activity of cytokines. The paw oedema inhibition by diphenhydramine, but not by meclizine, may suggest a different mechanism, which is independent of the effect of histamine. These data indicate that allergic oedema is more sensitive to anti-serotonin drugs, mainly anti-5-HT2, suggesting that the principal mediator of this inflammatory response is serotonin.
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Ten patients, 4 with nonproliferative diabetic retinopathy and 6 age-matched, nondiabetic controls, were studied by a noninvasive system to index choroidal blood flow. Pentoxifylline was administered daily at an oral dose of 400 mg tid in the diabetic patients for nine months.
Non-alcoholic fatty liver disease is increasingly being diagnosed worldwide and considered to be the commonest liver disorder in Western countries. It comprises a disease spectrum ranging from simple steatosis (fatty liver) through non-alcoholic steatohepatitis (NASH) to fat with fibrosis and, ultimately, cirrhosis. Simple steatosis is largely benign and non-progressive, whereas NASH can lead to cirrhosis, liver failure and hepatocellular carcinoma. Therapeutic strategies can be divided into those directed at components of the metabolic syndrome with potential beneficial liver effects and those directed specifically at the liver. Recent data suggest that diet and exercise improve NASH, particular in those achieving >7% weight loss. Obesity surgery has been shown to improve steatosis in all studies and inflammation and fibrosis in some. With respect to anti-diabetic drugs, results for metformin have not been convincing and concerns over the safety of glitazones have reduced the initial enthusiasm for their use. ACE inhibitors and angiotensin II receptor blockers hold the most promise as anti-hypertensive agents for patients with NASH and hypertension. With respect to more specific liver-directed therapies, there have been promising studies of antioxidants, including betaine and probucol, and vitamin E may improve NASH in adults and children. The TNF-α-lowering agent pentoxifylline may have beneficial effects on NASH. Liver transplantation is successful, but the disease recurrence rate is high in the absence of treatment of the underlying metabolic syndrome.
TNF-alpha, including other proinflammatory cytokines alone or in combination, induces iNOS expression and upregulates inflammatory responses. We evaluated the relationship between TNF-alpha and iNOS expression in indomethacin-induced jejunoileitis in male Sprague-Dawley rats. Rats were fed a daily dose of a phosphodiesterase inhibitor-either theophylline or pentoxifylline-for 2 days. Jejunoileitis was induced with two subcutaneous injections of indomethacin (7.5 mg/kg) 24 hr apart and theophylline or pentoxifylline continued for 12 hr or 4 days. Other rats received a single intraperitoneal injection of anti-TNF-alpha monoclonal antibody (TNF-Ab) 30-min before indomethacin. At 4 days TNF-Ab, theophylline, or pentoxifylline treatment significantly decreased indomethacin-induced ulceration, myeloperoxidase activity, and disease activity index. Although indomethacin significantly increased serum TNF-alpha and nitrate/nitrite levels over the control value as early as 12 hr, iNOS expression was detected only after 4 days. Serum IL-1beta level did not change at 12 hr but increased fourfold at 4 days. Treatment with TNF-Ab, theophylline, or pentoxifylline significantly reduced serum/tissue TNF-alpha, IL-1beta, nitrate/nitrite, and iNOS expression. The downregulation of nitrate/nitrite by these inhibitors suggests that TNF-alpha modulates iNOS expression.
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Sperm motility patterns of cryopreserved domestic cat ejaculates treated at 37 degrees C with 1 mM caffeine, pentoxifylline, or 2'-deoxyadenosine were analyzed using computer-assisted semen analysis (CASA). The percent motility (MOT), curvilinear velocity (VLC), straight-line velocity (VSL), linearity (LIN), and amplitude of lateral head displacement (ALH) were measured for each group following 15 min of treatment. Motility indices were examined during a 6-h treatment period to determine the effect of each chemical on sperm longevity. Caffeine, pentoxifylline, and 2'-deoxyadenosine each increased (p > .05) the MOT and VCL of the ejaculates compared to the controls. The longevity of the treated and control samples were not significantly different throughout the incubation period. These results, similar to previous findings with cryopreserved epididymal cat sperm, demonstrate that motility stimulants can significantly elevate the MOT and VCL of cryopreserved ejaculated cat sperm without having deleterious effects on longevity.
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In 1985, investigators reported that four months of pentoxifylline therapy resulted in a significant decrease in proteinuria (46 percent reduction) and plasma fibrinogen concentrations (18 percent reduction) in patients with diabetes. Our study evaluated four normotensive patients with diabetes and documented proteinuria who were treated with pentoxifylline 400 mg tid for four months. A consistent decrease in proteinuria (as measured by the urine protein/creatinine ratio) and plasma fibrinogen concentrations was not observed. Therapy with pentoxifylline was discontinued after four months.
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The significance of potential second messengers as mediators of the metabolic effects of tumor necrosis factor (TNF) was explored by studying their role in stimulating hepatic lipogenesis. Platelet-activating factor and prostaglandins have previously been suggested to mediate some of the toxic effects of TNF. An inhibitor of platelet-activating factor (WEB 2086) and two inhibitors of the synthesis of prostaglandins (ibuprofen and aspirin) had no effect on the ability of TNF to increase hepatic lipogenesis or serum triglyceride levels in the rat. Another inhibitor of the toxic effects of TNF, pentoxifylline, also had no effect on lipid metabolism in the rat. Catecholamines are increased after TNF administration, but alpha- and beta-adrenergic blockade did not prevent the lipogenic effects of TNF. However, interleukin 6, a cytokine whose synthesis and secretion are induced by TNF, is able to acutely stimulate hepatic lipogenesis in mice. Interleukin 6 stimulates hepatic lipogenesis by increasing hepatic citrate concentrations, the same mechanism by which TNF stimulates hepatic lipogenesis. These data suggest that interleukin 6, but not platelet-activating factor, prostaglandins, or catecholamines, could potentially mediate the lipogenic effects of TNF.
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To analyse the safety and efficacy of pentoxifylline sustained-release (PTX-SR) treatment in patients with early chronic Peyronie's disease (PD).